Folate and homocysteine are essential components of one-carbon metabolism. Diminished folate and increased homocysteine plasma levels are associated with colorectal cancer (CRC) and breast cancer particularly among those who consume moderate to high levels of alcohol, which interferes with one-carbon metabolism. Less than 10% of the genetic variance in the heritable levels of plasma folate and plasma homocysteine can be explained. Therefore we propose to conduct a cost-effective multistage analysis of genome-wide data on plasma folate and homocysteine levels among 1,629 women in the National Cancer Institute sponsored Cancer Genetic Markers of Susceptibility project, perform 2.5 million SNP imputations based on haplotype structure and combine these data with data from participants in the National Heart Lung and Blood Institute's Framingham SNP-Health Association Resource study. This proposal incorporates systematic association testing of common genetic variation including known associations and identifying novel pathways. We will replicate a subset of the highest-ranking SNPs from the hypotheses generated in the initial analysis in 960 women and explore the most promising SNP associations with risk of CRC and adenoma (CRA). As the first genome-wide association study of plasma folate and homocysteine, these data will provide an integrated research paradigm that synthesizes genome-wide analytic approaches and metabolic profiling to offer an informative platform for understanding gene-nutrient relationships and their potential association with CRC and CRA. Our empirical characterization of genetic variation in plasma levels of folate and homocysteine will provide insight for cancer prevention strategies and elucidate which population subgroups may benefit most from additional folate intake or supplementation due to genetic variation in B-vitamin metabolism or absorption.